PROJECT SUMMARY/ABSTRACT Triple negative breast cancer (TNBC) is a very aggressive subtype with limited therapeutic options. Intriguingly, women of African American (AA) origin have much higher TNBC-related mortality rates compared to European American (EA) women. This difference is evident even after adjusting for socioeconomic status and access to care, indicating a biological basis. TNBC tumors in AA women exhibit higher rate of growth and metastasis in comparison to TNBC in EA women. There is an urgent need to understand the molecular mechanisms involved in aggressive progression and increased metastatic potential of AA-TNBC. In our preliminary studies, we observed that AA-TNBC cells have higher invasion and migration potential in comparison to EA-TNBC cells showing inherently aggressive nature of AA-TNBC. In a preliminary screen, we found that a large percentage of AA-TNBC tumors exhibit loss-of-tumor suppressor Liver Kinase B1 (LKB1) in comparison to EA-TNBC tumors. Our preliminary microarray studies also found that LKB1-loss in AA-TNBC results in activation of oncoproteins- YAP and TAZ. Our data suggest that with inherent loss of LKB1, AA-TNBC gain `an oncogenic input' in the form of activated YAP-TAZ signaling. Using in vitro studies, clinical AA-TNBC and EA-TNBC samples and patient-derived xenograft (PDX) models, we will test our hypothesis that inherent LKB1-loss in AA-TNBC results in activation of oncogenic YAP-TAZ signaling leading to aggressive progression and increased metastatic potential of AA-TNBC. Our novel findings also suggest that AA-TNBC tumors may be vulnerable to therapeutic strategies directed at YAP-TAZ inhibition. Based on our strong preliminary data, we will investigate how loss of LKB1 in AA-TNBC might lead to acquisition of higher YAP-TAZ, and drive growth and metastasis of AA-TNBC cells. We will also analyze AA-TNBC and EA-TNBC tumors to establish LKB1-loss and elevated YAP-TAZ as biomarkers of aggressive progression of AA-TNBC. We will utilize these biological insights to test and propose safe and effective therapeutic strategies to target AA-TNBC. Using patient-derived xenograft (PDX) models, we propose to investigate whether AA-TNBCs are particularly susceptible to YAP-TAZ inhibition strategies and whether currently clinically available drugs (screened from a drug library) can be repurposed to target YAP-TAZ in AA-TNBC. Secondly, we plan to examine whether Honokiol, a natural compound from Magnolia grandiflora, (selected from a screen of known bioactive compounds) and its novel analogs have the potential to inhibit YAP-TAZ in AA-TNBC. Our studies will provide new understanding how loss-of-LKB1 and gain-of-YAP-TAZ in AA-TNBC form a relentless axis that drives AA-TNBC. These studies will provide novel insight into molecular mechanisms underlying racial disparity in TNBC and provide a novel set of biomarkers and potential drug-targets to develop novel ways to reduce the disparity in clinical outcome of AA and EA TNBC patients.